Programmed death-ligand 1 expression in carcinoma of unknown primary.

We examined the expression of programmed death-ligand 1 (PD-L1) in carcinoma of unknown primary (CUP) and its potential implications. Tissue microarrays were constructed for 72 CUP cases (histologic subtypes: 22 adenocarcinoma, 15 poorly differentiated carcinoma, 19 squamous cell carcinoma, and 14 undifferentiated carcinoma; clinical subtype: favorable type 17 [23.6%], unfavorable type 55 [76.4%]), with immunohistochemical staining performed for PD-L1 (22C3, SP142, SP263, and 28 - 8), CK7, and CK20 to determine the association between staining results and clinicopathological parameters. In CUP, the PD-L1 positivity rate was 5.6-48.6% (tumor cells [TC] or tumor proportion score [TPS]: 5.6-36.1%, immune cell score [IC]: 8.3-48.6%, combined positive score [CPS]: 16.7%) using different cutoff values for 22C3 (TPS ≥ 1%, CPS ≥ 10), SP142 (TC ≥ 50%, IC ≥ 10%), SP263, and 28 - 8 (TC and IC ≥ 1%). PD-L1 SP142 TC and PD-L1 SP263 IC showed the lowest (5.6%) and highest (48.6%) positivity rates, respectively. The PD-L1 positivity rate did not significantly differ based on the histologic subtype, clinical subtype, or CK7/CK20 across clones. Considering TC κ ≥ 1%, TC κ ≥ 50%, IC κ ≥ 1%, and IC κ ≥ 10%, the PD-L1 positivity rate was TC = 4.2-36.1% and IC = 9.7-48.6%; the overall agreement between antibodies ranged from 69.4 to 93.1%, showing fair or better agreement (κ ≥ 0.21). In CUP, PD-L1 positivity varied depending on antibodies and scoring systems, with no difference observed according to histologic or clinical subtypes.

Exploring the biological hallmarks of cancer of unknown primary: where do we stand today?

Cancer of unknown primary (CUP) affects a small percentage of the general population. Nonetheless, a substantial number of these patients have a poor prognosis and consequently succumb to their illness within a year of diagnosis. The natural history of CUP is characterised by early metastasis from the unknown primary site, aggressive course and resistance to conventional chemotherapy. Unfortunately, the processes by which this orphan disease originates and progresses have not been fully elucidated and its biology remain unclear. Despite the conceptual progress in genetic and molecular profiling made over the past decade, recognition of the genetic and molecular abnormalities involved in CUP, as well as the identification of the tissue of origin remain unresolved issues. This review will outline the biology of CUP by exploring the hallmarks of cancer in order to rationalise the complexities of this enigmatic syndrome. This approach will help the reader to understand where research efforts currently stand and the pitfalls of this quest.

Identifying primary site of lung-limited Cancer of unknown primary based on relative gene expression orderings.

BACKGROUND: Precise diagnosis of the tissue origin for metastatic cancer of unknown primary (CUP) is essential for deciding the treatment scheme to improve patients' prognoses, since the treatment for the metastases is the same as their primary counterparts. The purpose of this study is to identify a robust gene signature that can predict the origin for CUPs. METHODS: The within-sample relative gene expression orderings (REOs) of gene pairs within individual samples, which are insensitive to experimental batch effects and data normalizations, were exploited for identifying the prediction signature. RESULTS: Using gene expression profiles of the lung-limited metastatic colorectal cancer (LmCRC), we firstly showed that the within-sample REOs in lung metastases of colorectal cancer (CRC) samples were concordant with the REOs in primary CRC samples rather than with the REOs in primary lung cancer. Based on this phenomenon, we selected five gene pairs with consistent REOs in 498 primary CRC and reversely consistent REOs in 509 lung cancer samples, which were used as a signature for predicting primary sites of metastatic CRC based on the majority voting rule. Applying the signature to 654 primary CRC and 204 primary lung cancer samples collected from multiple datasets, the prediction accuracy reached 99.36%. This signature was also applied to 24 LmCRC samples collected from three datasets produced by different laboratories and the accuracy reached 100%, suggesting that the within-sample REOs in the primary site could reveal the original tissue of metastatic cancers. CONCLUSIONS: The result demonstrated that the signature based on within-sample REOs of five gene pairs could exactly and robustly identify the primary sites of CUPs.

A pitfall of bilateral inferior petrosal sinus sampling in cyclic Cushing's syndrome.

BACKGROUND: Clinical care of patients with cyclic Cushing's syndrome (CS) is challenging. Classical pitfalls include incorrect subtyping, unnecessary surgical procedures and delayed definite treatment. CASE PRESENTATION: A 43-year-old female suffered from a rapidly cycling ectopic CS. She experienced six cycles of severe hypercortisolism within a 2 year period (maximum plasma cortisol 5316 nmol/L, normal range 124.2-662.4 nmol/L; maximum urinary free cortisol 79,469 nmol/24 h, normal range < 414 nmol/24 h) lasting 2-9 weeks. The episodes were associated with pronounced hypokalemia (lowest K+ value recorded 2.4 mmol/l) and progressive signs and symptoms of CS. A bilateral inferior petrosal sinus sampling (BIPSS) performed during a trough phase was false positive for pituitary ACTH overproduction resulting in unnecessary transsphenoidal surgery while a second BIPSS performed during an active phase was indicative for ectopic CS. The 18F-DOPA PET/CT showed a pancreatic lesion, which was subsequently partially removed. Surprisingly, the histopathology was conclusive for ACTH-positive lymph node metastasis located in the retro-duodenal tissue of an occult neuroendocrine tumor WHO grade II. The primary tumor has not been identified so far and, because of the persistent hypercortisolism, the patient underwent bilateral adrenalectomy. Two years later, ACTH levels started to increase progressively. Percutaneous biopsy of a newly identified suspected lesion in the fifth thoracic vertebra revealed a metastasis with positive staining for ACTH, synaptophysin and chromogranin A. Therapy with carboplatin and etoposide was started and, since then, the patient underwent 12 cycles of chemotherapy. CONCLUSIONS: We report the challenging case of a rapidly cycling CS secondary to ACTH-secreting neuroendocrine intestinal tumor of unknown primary. We highlight the importance of performing diagnostic tests only during the phases of active cortisol secretion and as soon as first symptoms appear to avoid pitfalls.

Combined p16 and p53 expression in cervical cancer of unknown primary and other prognostic parameters : A single-center analysis.

BACKGROUND AND PURPOSE: Cervical cancer of unknown primary (CUP) represents an uncommon and heterogeneous subentity of head and neck cancer. However, both optimal diagnostics and therapy remain unclear. An improved understanding of the underlying pathology is essential to enable future tailored therapies and optimized outcomes. MATERIALS AND METHODS: We retrospectively analyzed 53 patients with head and neck CUP and 48 available cervical lymph node specimens. All patients have received radiotherapy between 2007 and 2015. Preradiotherapy involved lymph node specimens were analyzed for p16 and p53 immunoreactivity. The prognostic relevance of the combined p16 and p53 status and other clinical parameters were examined by univariate and multivariate analyses. RESULTS: Median patient age was 61.5 years and median irradiation dose to the involved nodal levels was 66 Gy. Of the 48 evaluated specimens, 13 (27%) were p16-positive and 31 (64.6%) p53-positive. After a median follow up of 32.9 months, patients with p16-negative and simultaneously p53-positive tumors showed a significantly inferior tumor-specific survival (TSS) compared to those with either p16+/p53-, p16+/p53+, or p16-/p53- (univariate: p = 0.055, multivariate: p = 0.038). Other factors with an adverse impact on TSS in the univariate analysis were smoking history (p = 0.032) and nodal stage (p = 0.038). CONCLUSIONS: The combined p16- and p53-expression status in cervical metastases of CUP may represent a simple method for risk stratification. Further validation of these biomarkers in large prospective trials is essential to design rational trials for CUP treatment optimization.

Metastatic neuroendocrine carcinoma in the skin.

Cutaneous metastases secondary to neuroendocrinetumors are rare. Herein we report a case of a 75-yearoldwoman who presented with a rare cutaneousmetastatic disease. She was previously diagnosed withmetastatic neuroendocrine carcinoma of unknownprimary, with metastases to liver, lung, and bone.Biopsy of the skin lesion demonstrated archetypicalpathology and positive immunohistochemicalstaining for chromogranin A and synaptophysin. Thepatient started palliative chemo-radiation therapyand passed away soon after.

AKT as Locus of Cancer Unknown Primary Site.

Cancer of unknown primary site is a metastasis developed by the positive feedback loops of primary cancer forming extreme cancer robustness. Such robustness occurs only in metastatic cancer or in relapsed lymphoma, myeloma, plasmocytoma, or leukemia. However, when it develops in primary cancer, hypoxic microenvironment generates positive feedback loops which hyperactivate AKT locus, forming extreme robustness that forcing cancer cells to migrate to the distant site, but primary cancer loosing that property or remains silent. Positive loops are the force and principal mechanism of metastasis development. A cancer cell is converted normal cell. Conversion occurs at the AKT genomic locus. Thus, cancer is genomic disease rather than disease of the specific organs. Targeting such locus by the locus chemotherapy (redox balance change) rather than by organ specific therapy results in conversion of positive loops into negative and disappearance of extreme robustness and malignant phenotype of the cancer unknown primary origin.

Tyrosine kinase inhibitor sunitinib therapy is effective in the treatment of bone metastasis from cancer of unknown primary: Identification of clinical and immunohistochemical biomarkers predicting survival.

Bone metastasis from cancer of unknown primary (BMCUP) brings poor survival prognosis and its management remains controversial. Sunitinib (SUTENT) proved effective in many sorts of solid tumors but has never been applied for patients with occult primary cancers, and there is no study to identify sensitive or resistant biomarkers for sunitinib therapy in CUP patients. An analysis was carried out to investigate the efficacy of sunitinib by multivariate survival analysis of 286 patients with BMCUP. We further carried out multivariate analysis to identify histological and clinical biomarkers that could predict sensitivity or resistance for sunitinib therapy. Of the 286 patients included from January 2011 to March 2016, sunitinib therapy proved effective to prolong survival in patients with BMCUP. Sensitive and resistant biomarkers were identified in histological specimen of patients receiving sunitinib therapy. Clinical factors were also identified that predict poor survival prognosis for sunitinib therapy. Sunitinib therapy proved effective to prolong survival in patients with BMCUP. Sensitive markers for sunitinib therapy include KDR positivity and early-developed treatment-induced hypertension. Resistance factors for sunitinib include VEGF positivity, CAIX positivity and squamous cell carcinoma pathology type. Prolonged symptom time and severe weight loss before therapy seemed to be associated with poor survival prognosis for sunitinib therapy.

Prognostic significance of WNT and hedgehog pathway activation markers in cancer of unknown primary.

BACKGROUND: Cancer of unknown primary (CUP) possesses distinct biology and peculiar natural history, in which the roles of the winged and hedgehog signalling pathways are unclear. MATERIALS AND METHODS: We constructed tissue microarrays and studied the immunohistochemical (IHC) expression of ß-catenin, smoothened (SMO) and the transcription factors TCF, LEF, GLI1 in 87 CUP cases for prognostic significance. RESULTS: A low rate of IHC expression of proteins was seen, the cut-off used being any expression in ≥ 1% of tumour cells. At univariate analysis, only nuclear IHC SMO expression displayed a statistically significant association with favourable outcome [median Overall survival (OS) of 19 months in SMO-positive vs. 12 months in SMO-negative cases, P = 0·01]. An activated Wnt pathway, defined as IHC expression of any of nuclear ß-catenin, TCF and LEF, was significantly associated with favourable progression free survival (median 9 vs. 5 months, P = 0·037) and OS (median 19 vs. 13 months, P = 0·04). This prognostic impact on OS was mainly driven by nuclear expression of TCF and/or LEF (P = 0·03). No prognostic significance of the hedgehog pathway activation status, defined as IHC expression of SMO or nuclear GLI1, could be established. A favourable prognostic impact of the concurrent activation of both pathways was observed. A trend for association of activated Wnt with response to chemotherapy (responders 67% among activated Wnt cases vs. 35% among nonactivated Wnt cases, P = 0·07) was observed in CUP adenocarcinomas. CONCLUSIONS: Activation of the Wnt pathway was a positive prognostic factor in a small CUP series, possibly via enhanced chemosensitivity. Independent validation is warranted.

Metastatic carcinoma of unknown primary: diagnostic approach using immunohistochemistry.

Carcinoma of unknown primary origin (CUP) is one of the 10 most prevalent malignancies. CUP patients in whom a site of origin can be ascribed have better outcomes than those in which the primary tumor remains unidentified. Among the tools available to pathologists in approaching these lesions, immunohistochemistry is a reliable, inexpensive, and widely available resource. New markers continue to emerge, which, in combination with other historically useful antibodies, allow rapid and accurate identification of primary site in an increasing number of cases. This review discusses the approach to the diagnosis of CUP using immunohistochemistry and outlines some of the most useful markers with a particular focus on the utility of lineage-restricted transcription factors, including CDX2, NKX3-1, PAX8, SATB2, TTF-1, and SF1.

Merkel cell carcinoma of lymph node with unknown primary has a significantly lower association with Merkel cell polyomavirus than its cutaneous counterpart.

Rare cases of Merkel cell carcinoma have been encountered in lymph nodes with unknown extranodal primary, which exhibit similar morphologic and immunophenotypic features to those in primary cutaneous Merkel cell carcinomas. However, it is uncertain whether the nodal Merkel cell carcinoma is a primary tumor of the lymph node or represents a metastasis from an occult or regressed extranodal lesion. To establish an accurate diagnosis of the nodal Merkel cell carcinoma can be challenging because of significant morphologic mimics, including lymphoblastic lymphoma and metastatic small cell carcinoma. Moreover, there is no consensus for a diagnostic term, and many different terms have been used, which can be confusing and may not fully reflect the nature of nodal Merkel cell carcinoma. In this study, we investigated the detailed clinicopathologic features of 22 nodal Merkel cell carcinomas, with comparison to 763 primary cutaneous cases retrieved from the literature. Overall, the nodal and cutaneous Merkel cell carcinomas shared similar clinical presentations, morphologic spectrum, and immunophenotype; both were mostly seen in elderly male with a typical neuroendocrine morphology. Most of cases expressed CK20, synaptophysin, and chromogranin A; and PAX5 and TdT were also positive in majority of cases. However, nodal Merkel cell carcinomas had a significantly lower association with Merkel cell polyomavirus than cutaneous cases (31% vs 76%, P=0.001). Therefore, these two entities may arise from overlapping but not identical biological pathways. We also recommend the use of the diagnostic term 'Merkel cell carcinoma of lymph node' to replace many other names used.

Metabolic phenotypes in primary unknown metastatic carcinoma.

BACKGROUND: The purpose of this study is to evaluate expression of metabolism-related proteins in primary unknown metastatic carcinoma (PUMC) and associated implications for treatment. METHODS: A tissue microarray containing 77 cases of PUMC was constructed and immunohistochemical staining was used to evaluate expression of the following proteins: Glycolysis-related: Glut-1, carbonic anhydrase (CA) IX, and monocarboxylate transporter (MCT) 4; Glutaminolysis-related: glutaminase1 (GLS1), glutamate dehydrogenase (GDH), and amino acid transporter-2 (ASCT2); and Mitochondrial-related: ATP synthase, succinate dehydrogenase (SDH)A, and SDHB. The association between immunohistochemical staining results and clinicopathologic parameters was evaluated. RESULTS: The expression of metabolism-related proteins was different depending on the histologic subtype. Compared to other subtypes, squamous cell carcinomas (SQ) expressed more Glut-1 (p = 0.028), while adenocarcinomas (AD) expressed more SDHB in the stroma (p = 0.025). The expression of metabolism-related proteins was also different depending on the clinical subtypes. Glut-1 was expressed most in the nodal type and the least in carcinomatosis type, when compared to other subtypes (p = 0.021). The metabolic phenotypes also showed other trends: when the stroma showed no glutaminolysis, the tumor mostly invaded lymph node, bone, and brain, while the tumor invaded regions other than lymph node, bone, and brain when the stroma showed glutaminolysis (p = 0.003). When the stroma showed the mitochondrial metabolic type, the histologic subtype was mainly AD, but the non-mitochondrial type was associated more with SQ (P = 0.049). CONCLUSION: For PUMC, the expression of metabolism-related proteins, such as Glut-1 and SDHB, differs in the tumor or stroma depending on the clinical and histologic tumor subtype.

Clinical features of human papilloma virus-related head and neck squamous cell carcinoma of an unknown primary site.

PURPOSE: Head and neck squamous cell carcinoma of an unknown primary site (HNSCCUP) is a heterogeneous group of tumors that includes the human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma. To investigate the relationship between HNSCCUP and HPV, we reviewed p16 overexpression and HPV DNA in lymph node metastases and examined their correlation with the primary site and clinical features. MATERIALS AND METHODS: Thirty-three patients with HNSCCUP were retrospectively studied. Dissected neck metastases were analyzed for p16 overexpression by immunohistochemistry, and the presence of HPV DNA was investigated by in situ hybridization. RESULTS: Of the 33 patients, 8 (24%) exhibited p16 overexpression. p16-positive lymph node metastases contained significantly more HPV DNA and were most frequently associated with occult primary lesions in the oropharynx and a favorable prognosis. Patients with a lower alcohol consumption, only level II/III metastasis, and cystic lymph node metastasis tended to have p16 overexpression. CONCLUSIONS: This is the first report on the relationship of HNSCCUP with p16 and HPV DNA status in Asian patients. In total, 24% of the HNSCCUP patients were p16 positive. p16 overexpression in neck metastasis was predictive of both an occult primary lesion in the oropharynx and an association with HPV infection. Alcohol consumption, location, and features of neck metastasis were correlated with p16 expression.

[The role of pathology in the diagnostics of CUP syndrome]. / Die Rolle der Pathologie in der Diagnostik des CUP-Syndroms.

Cancers of unknown primary (CUP) origin account for 2-3 % of all malignancies in Germany and represent a heterogeneous, often aggressive and clinically challenging group of tumors with early metastatic dissemination for which a standardized diagnostic work-up initially fails to identify the primary site of origin at the time of diagnosis. This article reviews the options and challenges of tissue-based conventional as well as molecular diagnostic procedures to categorize this heterogeneous group of neoplasms. The role of pathology in the diagnostics of CUP syndrome is described as part of a multidisciplinary effort involving oncologists, surgeons and radiologists with the ultimate goal of assisting clinical reasoning and decision-making.

[Structured diagnostics and therapy of the CUP syndrome]. / Strukturierte Diagnostik und internistische Therapie des CUP-Syndroms.

BACKGROUND: In the majority of cases, patients with cancer of unknown primary (CUP) have a poor prognosis with no prospect of being cured. Hence, a reasonable focus of diagnostics on its essential targets seems appropriate. PATIENTS: Particularly important is the identification of all patients who can be assigned to subgroups with a favorable prognosis and who might benefit from a specific therapy. For all other patients, platinum-based combination therapy is the standard cytostatic therapy. THERAPY: In addition to platinum derivatives, taxanes, gemcitabine and irinotecan can also be used. Promising innovative approaches include targeted therapies, in particular bevacizumab and erlotinib, and identification of the tissue origin with micro-RNA or gene expression analyses which can help identify the most suitable organ-specific therapy for individual patients. PERSPECTIVES: It would be desirable if the group of patients treated with unspecific therapy could be reduced by improved diagnostics so that these patients could be treated with organ-specific therapy or with molecularly targeted approaches. Micro-RNA and gene expression analyses appear to be interesting for this purpose. Another complementary approach is to improve the treatment results of patients receiving an unspecific standard combination therapy by additional administration of new targeted substances.

Tracing unknown tumor origins with a biological-pathway-based transformer model.

Cancer of unknown primary (CUP) represents metastatic cancer where the primary site remains unidentified despite standard diagnostic procedures. To determine the tumor origin in such cases, we developed BPformer, a deep learning method integrating the transformer model with prior knowledge of biological pathways. Trained on transcriptomes from 10,410 primary tumors across 32 cancer types, BPformer achieved remarkable accuracy rates of 94%, 92%, and 89% in primary tumors and primary and metastatic sites of metastatic tumors, respectively, surpassing existing methods. Additionally, BPformer was validated in a retrospective study, demonstrating consistency with tumor sites diagnosed through immunohistochemistry and histopathology. Furthermore, BPformer was able to rank pathways based on their contribution to tumor origin identification, which helped to classify oncogenic signaling pathways into those that are highly conservative among different cancers versus those that are highly variable depending on their origins.

Screening for occult malignancy with FDG-PET/CT in patients with unprovoked venous thromboembolism.

Extensive screening strategies to detect occult cancer in patients with unprovoked venous thromboembolism (VTE) are complex and no benefit in terms of survival has been reported. FDG-PET/CT (2-[F-18] fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography), a noninvasive technique for the diagnosis and staging of malignancies, could be useful in this setting. Consecutive patients ≥ 50 years with a first unprovoked VTE episode were prospectively included. Screening with FDG-PET/CT was performed 3-4 weeks after the index event. If positive, appropriate diagnostic work-up was programmed. Clinical follow-up continued for 2 years. Blood samples were collected to assess coagulation biomarkers. FDG-PET/CT was negative in 68/99 patients (68.7%), while suspicious FDG uptake was detected in 31/99 patients (31.3%). Additional diagnostic work-up confirmed a malignancy in 7/31 patients (22.6%), with six of them at early stage. During follow-up, two patients with negative FDG-PET/CT were diagnosed with cancer. Sensitivity (S), positive (PPV) and negative predictive values (NPV) of FDG-PET/CT as single tool for the detection of occult malignancy were 77.8% (95% CI: 0.51-1), 22.6% (95% CI: 0.08-0.37) and 97.1% (95% CI: 0.93-1), respectively. Median tissue factor (TF) activity in patients with occult cancer was 5.38 pM vs. 2.40 pM in those without cancer (p = 0.03). Limitation of FDG-PET/CT screening to patients with TF activity > 2.8 pM would improve the PPV to 37.5% and reduce the costs of a single cancer diagnosis from 20,711€ to 11,670€. FDG-PET/CT is feasible for the screening of occult cancer in patients with unprovoked VTE, showing high S and NPV. The addition of TF activity determination may be useful for patient selection.

A practical approach to immunohistochemical diagnosis of ovarian germ cell tumours and sex cord-stromal tumours.

Immunohistochemistry can be useful in the diagnosis of ovarian germ cell tumours and sex cord-stromal tumours. A wide variety of markers are available, including many that are novel. The aim of this review is to provide a practical approach to the selection and interpretation of these markers, emphasizing an understanding of their sensitivity and specificity in the particular differential diagnosis in question. The main markers discussed include those for malignant germ cell differentiation (SALL4 and placental alkaline phosphatase), dysgerminoma (OCT4, CD117, and D2-40), yolk sac tumour (α-fetoprotein and glypican-3), embryonal carcinoma (OCT4, CD30, and SOX2), sex cord-stromal differentiation (calretinin, inhibin, SF-1, FOXL2) and steroid cell tumours (melan-A). In addition, the limited role of immunohistochemistry in determining the primary site of origin of an ovarian carcinoid tumour is discussed.

Molecular diagnosis of the tissue of origin in cancer of unknown primary site: useful in patient management.

OPINION STATEMENT: Cancer of unknown primary site (CUP) is a clinicopathologic syndrome consisting of many types of cancer and accounting for approximately 3 % of all patients with advanced cancers. This syndrome has frustrated patients and physicians for decades, because a primary site or tissue of origin has not been possible to identify clinically, despite the presence of metastatic tumor. Favorable subsets (approximately 20 % of all CUP) with a presumptive occult primary site have been recognized for several decades based on clinical and standard pathologic features; site-specific therapy in these patients improves their survival compared with the majority of other (approximately 80 %) CUP patients. These other patients, most with adenocarcinomas, have been difficult to treat because the tissue of origin was unknown. Broad-spectrum empiric chemotherapy became the standard approach for these patients in the past 30 years. More recently, new diagnostic technology (evolving immunohistochemistry and emergent gene-expression profiling) has enabled us to establish accurately a tissue of origin in most (90 %+) CUP patients. Gene-expression profiling assays complement standard pathology and for the majority of biopsy specimens accurately identify the primary site or tissue of origin; clinical studies have supported the value of site-directed therapy. When the tissue of origin is in doubt after standard pathologic examination, a gene expression assay is frequently diagnostic, and the outcome of many CUP patients is improved with site-specific therapy. The era of empiric therapy has ended in favor of site-specific therapy, based on the precise diagnosis of the tumor type present in each patient.

Cancer stem cells and tumor dormancy.

The cancer stem cell hypothesis postulates that only a subpopulation of cancer cells in a tumor is capable of initiating, sustaining, and reinitiating tumors, while the bulk of the population comprises non-stem cancer cells that lack tumor initiation potential. The interactions of these two phenotypically distinct populations can provoke various nonlinear growth kinetics in the emerging tumor. An environmentally independent, intrinsic dormant state is an inevitable early tumor progression bottleneck within a range of biologically realistic cell kinetic parameters. In certain conditions, cell kinetics can combine to enable escape to tumor progression, yielding morphologically distinct self-metastatic expansion of multiple self-limiting tumor clones.